Phase I/II trial of perioperative avelumab in combination with chemoradiation (CRT) in the treatment of stage II/III resectable esophageal and gastroesophageal junction (E/GEJ) cancer.
Authors: Nataliya Volodymyrivna Uboha, Jens C. Eickhoff, James D. Maloney, Daniel McCarthy, Malcolm DeCamp, Dustin A. Deming, Noelle K. LoConte, Kristina A. Matkowskyj, Monica Arun Patel, Newton Hurst, Jeremy D. Kratz, Sam Joseph Lubner, Michael Frederick Bassetti
Journal: Journal of Clinical Oncology (2022)

4034 Background: Neoadjuvant CRT followed by surgery is the standard of care for patients (pts) with stage II/III E/GEJ cancer, yet recurrence rates remain high. Immunotherapy has demonstrated activity in advanced E/GEJ cancer and was recently approved for adjuvant treatment of early stage disease. This trial evaluated the safety and efficacy of avelumab with perioperative CRT in resectable E/GEJ cancer. Methods: This is a two part phase I/II trial. Phase I was a safety run-in of 6 pts. Phase II planned to enroll an additional 18 pts in an expansion cohort. Pts with E/GEJ adenocarcinoma or squamous cell cancer received CRT (41.4 Gy in 23 fractions) with weekly carboplatin and paclitaxel. Three doses of avelumab (10 mg/kg IV, q14 days) were administered starting on day 29 of treatment, to coincide with the last chemotherapy dose. Surgery was performed 8-10 weeks after CRT completion. Pts received 6 doses of avelumab after resection (10 mg/kg IV, q14 days). The primary endpoint of the Phase 1 was safety and tolerability. The primary endpoint of the Phase II was pathologic complete response (pathCR) rate, assessing patients from the safety run in and expansion cohorts. Results: Between 6/2018 and 10/2021, 22 pts (20 males, median age 64) enrolled in the study. Enrollment was stopped after 16 patients in the expansion cohort due to accrual delays and changes in standard treatment. 19/22 patients (86%) had adenocarcinoma; 15/22 (68%) had lymph node positive disease at diagnosis. 19 pts underwent successful resection while on study. 3 pts went off study before resection due to grade 3 avelumab-related infusion reaction (1), patient preference (1), and non-adherence (1). There were no unexpected surgical complications. 4 pts (21%) had R1 resection with 3/4 having positive radial margin and 1/4 positive proximal margin. At resection, 5 pts (26%) had pathCR (3/16 adenocarcinomas, 2/3 squamous cell), 4 ypT1N0 disease, and 14/19 were ypN0. 42% had tumor regression score of 0 or 1. The combination of CRT and avelumab had an acceptable toxicity profile. No grade ≥3 immune-related AEs were observed. Immune-related hypothyroiditis was seen in 2 patients (grade 2). Three patients had grade 2 infusion-related reaction, but were able to continue with treatment. 21/22 pts had reversible grade ≥3 lymphopenia; 13/22 grade ≥ 3 wbc decrease; 6/22 grade 3 neutropenia. As of data cutoff on 2/1/2022, 1 patient remains on study treatment, 15 in follow up, 5 expired, 1 off study. Additional efficacy data is being collected. Correlative studies are ongoing. Conclusions: Perioperative CRT with avelumab is well tolerated with no unexpected toxicities. Neoadjuvant chemoradiation with immunotherapy is a promising approach for patients with E/GEJ tumors. Additional safety, efficacy and correlative analysis from this study will be presented at the meeting. Clinical trial information: NCT03490292.